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Targeted Therapies in Metastatic Colorectal Cancer: An Update

Targeted Therapies in Metastatic Colorectal Cancer: An Update. ASCO 2007: Targeted Therapies in Metastatic Colorectal Cancer: An Update. Bevacizumab is effective in combination with XELOX or FOLFOX-4 Bevacizumab use beyond first progression linked to improvement in survival outcomes

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Targeted Therapies in Metastatic Colorectal Cancer: An Update

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  1. Targeted Therapies in Metastatic Colorectal Cancer: An Update

  2. ASCO 2007: Targeted Therapies in Metastatic Colorectal Cancer: An Update Bevacizumab is effective in combination with XELOX or FOLFOX-4 Bevacizumab use beyond first progression linked to improvement in survival outcomes Cetuximab in combination with FOLFIRI is an effective first-line therapy Panitumumab is generally well tolerated and has a consistent toxicity profile across studies FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan FOLFOX-4 = 5-fluorouracil/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin

  3. Bevacizumab is effective in combinationwith XELOX or FOLFOX-4 Bevacizumab (Bev) in combination with XELOX or FOLFOX-4: updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer Saltz L, et al. ASCO 2007: Abstract 4028.

  4. Background • Colorectal cancer is the second leading cause of death from cancer in Canada • Approximately 20,800 new cases of colorectal cancer will be diagnosed in 2007 alone1 • Monoclonal antibodies (MAbs) such as bevacizumab, cetuximab, and panitumumab in combination with chemotherapy drugs are showing considerable promise • Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that inhibits the vascular endothelial growth factor (VEGF), secreted by tumour cells to bring about new blood vessel formation • Cancer Care Ontario guidelines recommend the addition of bevacizumabto improve overall survival • As first-line therapy in patients with advanced colorectal cancer receiving 5-fluorouracil (5-FU)–based chemotherapy • As second-line therapy to patients who did not receive bevacizumab as part of their initial treatment2 1. Canadian Cancer Statistics, 2007. 2. Welch, et al. Cancer Care Ontario, 2005.

  5. Background(continued) • The NO16966 trial1 was started as a randomized phase III study to compare the efficacy of • XELOX (capecitabine and oxaliplatin) versus • FOLFOX-4 (5-fluorouracil, leucovorin, and oxaliplatin) • The protocol was amended to include bevacizumab in a partially blinded 2 x 2 factorial design to determine the following objectives: • Non-inferiority of XELOX versus FOLFOX-4 • Superiority of bevacizumab in combination with chemotherapy (XELOX and FOLFOX-4) versus chemotherapy alone for progression-free survival (PFS) 1. Saltz L, et al. ASCO 2007: Abstract 4028. .

  6. Study design • The study was a double-blind study with regard to bevacizumab and placebo administration • Enrolled patient criteria included: • ECOG PS ≤1 • Number of unidentified measurable lesions ≥1 • No prior systemic therapy for advanced metastatic colorectal cancer • No prior treatment with oxaliplatin or bevacizumab • Patients who had undergone prior adjuvant therapy should not have progressed during or within 6 months of completion Saltz L, et al. ASCO 2007: Abstract 4028. ECOG = Eastern Cooperative Oncology Group

  7. Study design(continued) FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin Saltz L, et al. ASCO 2007: Abstract 4028.

  8. Study design(continued) • Patients randomized to XELOX ± bevacizumab or FOLFOX-4 ± bevacizumab • XELOX + bevacizumab or placebo for 21-day cycle • Bevacizumab (or placebo) 7.5 mg/kg day 1 • Oxaliplatin 130 mg/m2 day 1 • Capecitabine 1,000 mg/m2 twice daily days 1–14 • FOLFOX-4 + bevacizumab or placebo for 14-day cycle • Bevacizumab (or placebo) 5 mg/kg day 1 • Oxaliplatin 85 mg/m2 day 1 • Folinic acid 200 mg/m2 days 1, 2 • Fluorouracil 400 mg/m2 bolus days 1, 2 — followed by 600 mg/m2 over 22 h • Primary endpoint was progression-free survival • Secondary endpoints were overall survival, response rate assessed according to RECIST; safety evaluated using NCI CTC v3.0 NCI CTC= National Cancer Institute Common Toxicity Criteria RECIST = response evaluation criteria in solid tumours Saltz L, et al. ASCO 2007: Abstract 4028.

  9. Key findings • Significant prolongation of progression-free survival (PFS) in the bevacizumab + oxaliplatin–based chemotherapy arm (HR = 0.83 [97.5% CI: 0.072–0.95]; p = 0.0023) • Trend toward prolonged overall survival (OS) • Higher proportion of discontinuation of therapy because of adverse effects (AEs) that occurred in the bevacizumab-containing arms versus the placebo-containing arms (31% versus 21%) • Most treatment discontinuations, however, due to chemotherapy rather than bevacizumab-related events • Most common reasons for treatment discontinuation: neurotoxicity, GI events, general disorders, and hematological events Saltz L, et al. ASCO 2007: Abstract 4028.

  10. Grade 3 or 4 events with chemotherapy ± bevacizumab Saltz L, et al. ASCO 2007: Abstract 4028.

  11. Key conclusions • Significant improvement in progression-free survival (PFS) with the addition of bevacizumab to front-line oxaliplatin-based chemotherapy • Analysis of ‘on treatment’ PFS versus ‘general’ PFS suggests that continuation of bevacizumab until disease progression may be necessary to optimize effect of bevacizumab on PFS • Observed overall survival (OS) difference did not reach statistical significance (p = 0.077) Saltz L, et al. ASCO 2007: Abstract 4028.

  12. Canadian perspective by Dr. Cripps • Equivalence of XELOX to FOLFOX-4 and FOLFOX-6 in both first-line and second-line chemotherapy • Infusional lines not needed with XELOX; this is especially relevant for pockets in Canada where infusional pumps not available • There are changing toxicities with XELOX versus FOLFOX, but toxicities can be managed easily • Recently completed phase I study1 found response rates of first-line capecitabine (X), irinotecan (I), and oxaliplatin (O) to be very high, overall survival 79%, disease control rate 92; five patients have gone in for surgical resection. XIO well tolerated • Targeted therapies are here to stay • Level 1 evidence suggests targeted therapy such as bevacizumab can add 4.4 months to progression-free survival • Now we need to confirm the efficacy and safety of XIO with and without bevacizumab in a phase II trial FOLFOX-4 = 5-fluorouraci/leucovorin/oxaliplatin FOLFOX-6 = infusional 5-fluorouracil/leucovorin/oxaliplatin XELOX = capecitabine/oxaliplatin 1. Maroun J, et al. ASCO 2007: Abstract 4086.

  13. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): results from a large observational study (BRiTE).Grothey A, et al. ASCO 2007: Abstract 4036. Bevacizumab use beyond first progression linked to improvement in survival outcomes .

  14. Background • No data exist regarding • Effects of bevacizumab beyond first progression (BBP) • Optimal duration of VEGF inhibition, including long-term safety and efficacy of using BBP • BRiTE is an observational, non-controlled bevacizumab treatment registry: • Initiated in 2004 • Evaluates safety and efficacy of bevacizumab in combination with chemotherapy in large, less-selected, community-based population of patients with previously untreated mCRC (metastatic colorectal cancer) BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects and Safety VEGF = vascular endothelial growth factor Grothey A, et al. ASCO 2007: Abstract 4036.

  15. Study design • Patients enrolled from 248 study sites in 49 states between February 2004 and June 2005: • Group of 1,953 evaluable patients • Metastatic or locally advanced and unresectable colorectal cancer • No prior therapy for their metastatic disease • Patients with poor ECOG PS also included in the study • Investigator decided on • Dose, schedule, and duration of bevacizumab • Dose, schedule and choice per duration of chemotherapy regimen • Primary endpoint: survival beyond first progression • Secondary endpoints: time to progression, and overall survival or study termination ECOG PS = Eastern Cooperative Oncology Group performance status Grothey A, et al. ASCO 2007: Abstract 4036.

  16. Key findings • In bevacizumab beyond first progression (BBP) subgroup: • Longer survival beyond first progression • Longer median overall survival • No appreciable difference in bevacizumab-associated safety events between BBP and No BBP subgroups • No appreciable increase in incidence of bevacizumab-associated safety events post–first progression observed in BBP subgroup: • Arterial thromboembolic events • Grade 3 or 4 bleeding events • GI perforation • No apparent increase in incidence of bevacizumab-specific adverse events (AEs) in BBP subgroup Grothey A, et al. ASCO 2007: Abstract 4036.

  17. Key conclusions • Median overall survival (OS) in BRiTE is 25.1 months, longer than OS previously reported from phase III trial AVF2107 (median OS 20.3 months), despite unselected population • Substantially longer median OS and survival beyond first progression in the BBP versus the No BPP subgroups • Similar overall rates of bevacizumab-associated safety events prior to first progression or after first progression in the BBP subgroup, compared to patients who received bevacizumab only • First report of improvement in survival outcomes associated with BBP for patients who started bevacizumab in first-line setting BBP = bevacizumab beyond first progression BRiTE = Bevacizumab Regimens: Investigation of Treatment Effects andSafety Grothey A, et al. ASCO 2007: Abstract 4036.

  18. Cetuximab in combination with FOLFIRI is an effective first-line therapy Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  19. Background • The epidermal growth factor receptor (EGFR) belongs to the human epidermal growth factor receptor (HER) family of transmembrane receptors • Aberrant cell signalling, mediated through EGFR, plays a pivotal role in tumorigenesis and disease progression • Monoclonal antibodies such as cetuximab and panitumumab prevent the binding of the epidermal growth factor and TGF-alpha to the EGFR, and bring about inhibition of cell proliferation1 • Common side effects of anti-EGFR therapy include skin toxicities such as acneiform dermatitis, pruritis, erythema, rash, and dry skin TGF = transforming growth factor 1. McKarney L, et al. New Evidence in Oncology 2006.

  20. Background (continued) • Appearance of skin rash may be useful as a surrogate marker of EGFR efficacy • Ongoing studies are attempting to elucidate characteristics of target rashes that may correlate with better anti-EGFR response • CRYSTAL trial initiated to investigate addition of cetuximab to FOLFIRI as first-line treatment EGFR-expressing metastatic colorectal cancer1 • The correlation of severity of skin toxicity with PFS was a secondary endpoint EGFR = epidermal growth factor receptor FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan TGF = transforming growth factor 1. Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  21. Study design • Patients (n = 1,217) enrolled from 32 countries had: • Histologically confirmed unresectable metastatic colorectal cancer • EGFR expression in primary tumour or metastasis as detected by IHC • Tumours ≥1 bi-dimensionally measurable lesion • No previous chemotherapy for metastatic disease; adjuvant therapy allowed if stopped minimum 6 months previous (no irinotecan) • ECOG PS ≤ 2 at study entry • Randomized 1:1 to receive either: • Group A: cetuximab plus FOLFIRI • QW: cetuximab: 400 mg/m2 initial dose, then 250 mg/m2/week • Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours, or • Group B: FOLFIRI alone • Q2W: irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours ECOG = Eastern Cooperative Oncology Group FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan IHC = immunohistochemistry Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  22. Study design(continued) • Patient population: • Total randomized patients (n = 1,217) • Population evaluated for safety (n = 1,202) • Intent to treat population (n = 1,198) • Primary endpoint: progression-free survival • Secondary endpoints: • Overall survival • Overall response rate (ORR) • Disease control rate (DCR) • QoL (EORTC QLQ C30) • Safety EORTC = European Organisation for Research and Treatment of Cancer QLQ C30 = Quality of Life Questionnaire QoL = quality of life Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  23. Key findings • Progression-free survival (PFS) found to be significantly prolonged with addition of cetuximab to FOLFIRI Subgroup analysis of PFS: • Pronounced PFS benefit seen in patients with metastases only to liver • More favourable PFS with cetuximab plus FOLFIRI in other subgroups, except for patients with ECOG PS 2 at baseline • Significantly longer median PFS for Group A versus Group B (8.9 months and 8 months, respectively, stratified log-rank p-value = 0.0479) (Table 1) ECOG PS = Eastern Cooperative Oncology Group performance status FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  24. Progression-free survival Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  25. Key findings(continued) • Significant increase in response rate with cetuximab (46.9% versus 38.7%, p = 0.0038) (Figure 1) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  26. Key findings(continued) • Significantly more patients underwent surgery with curative intent (p = 0.0034) and had successful resection in cetuximab arm (Figures 2 and 3) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  27. Key findings(continued) FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  28. Safety • Treatment generally well tolerated; neutropenia, diarrhea, and skin reactions most common grade 3 or 4 adverse events (Table 2) Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  29. Safety (continued) • More grade 3 skin reactions associated with cetuximab vs. control • Slightly higher incidence of diarrhea • Other adverse events, including neutropenia, comparable in groups • Better PFS outcomes associated with severity of skin reaction seen in cetuximab-treated patients. Median progression-free survival (PFS): • Grade 3 skin reactions: 11.3 months • Grade 2 skin reactions: 9.4 months • Grade 0 or 1 skin reactions: 5.4 months Van Cutsem E, et al. ASCO 2007: Abstract 4000

  30. Key conclusions • Significant increase in response rate and progression-free survival in the cetuximab plus FOLFIRI arm • Relative risk of progression reduced by approximately 15% in the cetuximab plus FOLFIRI group • Treatment-related side effects of cetuximab plus FOLFIRI as expected: moderate occurrence of diarrhea and significantly more frequent skin reactions compared to FOLFIRI alone FOLFIRI = infusional 5-fluorouracil/leucovorin/irinotecan Van Cutsem E, et al. ASCO 2007: Abstract 4000.

  31. Panitumumab is generally well tolerated and has a consistent toxicity profile across studies Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR), in patients (pts) with metastatic colorectal cancer (mCRC) across clinical trials Peeters M, et al. ASCO 2007: Abstract 4138.

  32. Background • Study presented pooled safety data of panitumumab monotherapy from ten phase I to III clinical trials1 • Many studies report clinical activity and tolerability of panitumumab in EGFR-expressing mCRC patients who had progressed during or after completion of chemotherapy with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens • Panitumumab: • Recombinant fully human IgG2 MAb • Binds specifically to the EGFR • Competitively inhibits the binding of ligands to receptor EGFR= epidermal growth factor receptor IgG = immunoglobulin G MAb = monoclonal antibody mCRC = metastatic colorectal cancer 1. Peeters M, et al. ASCO 2007: Abstract 4138.

  33. Study design • Pooled safety data from ten clinical studies (n = 966) of panitumumab monotherapy in patients with mCRC • Patients with mCRC and ECOG PS 0-2 included in study (one patient ECOG PS 3) • Primary endpoints: clinical safety events including • Incidence of adverse events, including skin-related toxicity and infusion reactions • Deaths • Drug exposure • Incidence of dose changes • Immunogenicity of panitumumab • Secondary endpoints: changes in metabolic and laboratory assessments after panitumumab infusions ECOG PS = Eastern Cooperative Oncology Group performance status mCRC = metastatic colorectal cancer Peeters M, et al. ASCO 2007: Abstract 4138.

  34. Study design(continued) • Panitumumab administered by infusion over 30 to 60 minutes per protocol; premedication not required. Dosing schedule shown in Table 1 Peeters M, et al. ASCO 2007: Abstract 4138.

  35. Key findings • Safety results summarized in Tables 2, 3, and 4 • Fifteen percent of patients (149) died during the study (including deaths within 30 days of last dose of panitumumab). Two deaths considered to be treatment related: • Pulmonary edema in patient with history of hypercoagulation, deep vein thrombosis, peripheral vascular disease, and diabetes mellitus • Myocardial infarction and cerebrovascular accident observed in patient with history of anemia, diabetes mellitus, deep vein thrombosis, hyperlipidemia, hypertension, and supraventricular tachycardia • Antibodies to panitumumab: patients who were predose negative and had persistent postdose positive results: • ELISA found 2/778 patients (0.3%) tested positive for anti-panitumumab antibodies • Biacore found 2/638 patients (0.4%) tested positive for anti-panitumumab antibodies • Bioassay determined 6/638 patients (1%) had neutralizing antibodies to panitumumab Peeters M, et al. ASCO 2007: Abstract 4138.

  36. Incidence of skin-related toxicity Peeters M, et al. ASCO 2007: Abstract 4138.

  37. Adverse events excluding skin-related toxicity Peeters M, et al. ASCO 2007: Abstract 4138.

  38. Infusion reactions reported per investigator Peeters M, et al. ASCO 2007: Abstract 4138.

  39. Key conclusions • Panitumumab generally well tolerated with consistent toxicity profile across studies • Common toxicities included fatigue, gastrointestinal side effects, and skin-related (majority were grade 1 or 2) • Grade 3 or 4 infusion reactions rare (0.4% of patients); no premedication required • Treatment-related adverse events of grade 3 or 4 reported in 20% patients • Four percent of patients permanently discontinued panitumumab or withdrew from study due to treatment-related adverse events • Anti-panitumumab antibody formation postdose was detected in <1% of patients by ELISA and Biacore • Incidence of skin-related adverse events in Figure 1 Peeters M, et al. ASCO 2007: Abstract 4138.

  40. Figure 1 : Any skin-related adverse events Peeters M, et al. ASCO 2007: Abstract 4138.

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